Proper energy allocation underlies metabolic health and requires the evolved cooperation of the mitochondrial and nuclear genomes, embedded in a context of diet. Human metabolic disease is increasingly viewed in the framework of energy homeostasis. Because energetic processes are highly conserved, this study of Drosophila addresses key issues for understanding human metabolic disease - the physiological consequences of mitochondrial-nuclear interactions and the role that diet plays in mediating energy metabolism. This project tests hypotheses regarding genetic relationships between energetic biochemical pathways, energy storage, metabolic rate and performance phenotypes 1) in healthy Drosophila, 2) in Drosophila with disrupted mito-nuclear genomes and 3) under normal and calorie- restricted diets. Mito-nuclear disruptions will be created by introgressing mtDNA from D. simulans into a D. melanogaster nuclear background. We will also quantify mRNA expression levels of regulatory genes involved in communication between genomes. The results will identify candidate enzyme-encoding and regulatory genes that can be further investigated for functional roles in maintaining metabolic health. [unreadable] [unreadable]